Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, 23507, USA.
The Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA, 23501, USA.
Sci Rep. 2024 Jul 8;14(1):15736. doi: 10.1038/s41598-024-65574-4.
Benign Prostatic Hyperplasia (BPH) is a complex condition leading to Lower Urinary Tract Symptoms in aging men, characterized by cellular proliferation, smooth muscle dysfunction, inflammation, and fibrosis. While BPH is known to involve heightened macrophage infiltration, the specific contribution of infiltrating monocytes/macrophages to the disease mechanism remains uncertain. This research explores the impact of reducing circulating monocytes and subsequently limiting their tissue infiltration by using Ccr2 knockout (Ccr2-KO) mice. Ccr2-KO and wild type mice were implanted with testosterone and estradiol (T + E2, 25 mg + 2.5 mg) pellets. Urinary function was assessed via weekly void spot assays over 12 weeks, and prostatic macrophage levels were visualized and quantified in tissue sections using an F4/80 antibody. Additionally, Ki-67 staining was used to evaluate cell proliferation, and picrosirius red staining to assess collagen accumulation. Increased voiding frequency which developed in T + E2 mice, was significantly ameliorated in Ccr2-KO mice, however, both Ccr2-KO and wild type (WT) mice showed increased bladder weights after three month, representing a hypertrophic response to bladder outlet obstruction. T + E2 substantially increased the density of macrophages in WT but not Ccr2-KO mouse prostate. Proliferation rate, as indicated by Ki-67 positivity, was elevated in the vental and anterior prostate lobes but was only marginally reduced in Ccr2-KO mice. Most importantly, a significant prostatic collagen accumulation was observed in WT mice that was markedly reduced by Ccr2 deficiency post T + E2 treatment. The absence of Ccr2 mitigates urinary dysfunction and alters prostatic macrophage levels and collagen accumulation in steroid hormone imbalance. These findings suggest a crucial role for monocyte infiltration, giving rise to macrophages or other cell derivatives, to drive fibrosis.
良性前列腺增生（BPH）是一种导致老年男性下尿路症状的复杂疾病，其特征是细胞增殖、平滑肌功能障碍、炎症和纤维化。虽然已知 BPH 涉及巨噬细胞浸润增加，但浸润单核细胞/巨噬细胞对疾病机制的具体贡献仍不确定。本研究通过使用 Ccr2 敲除（Ccr2-KO）小鼠来探索减少循环单核细胞并随后限制其组织浸润的影响。将 Ccr2-KO 和野生型小鼠植入睾丸酮和雌二醇（T+E2，25mg+2.5mg）丸。通过每周一次的尿液斑点检测评估尿功能，并用 F4/80 抗体在组织切片中可视化和量化前列腺巨噬细胞水平。此外，用 Ki-67 染色评估细胞增殖，用苦味酸红染色评估胶原积累。在 T+E2 小鼠中发展的排尿频率增加在 Ccr2-KO 小鼠中得到显著改善，然而，Ccr2-KO 和野生型（WT）小鼠在三个月后均表现出膀胱重量增加，代表对膀胱出口梗阻的肥大反应。T+E2 显著增加了 WT 但不是 Ccr2-KO 小鼠前列腺中巨噬细胞的密度。增殖率，如 Ki-67 阳性所示，在前腹叶和前腹叶中升高，但在 Ccr2-KO 小鼠中仅略有降低。最重要的是，在 WT 小鼠中观察到明显的前列腺胶原积累，在用 T+E2 治疗后 Ccr2 缺乏显著减少。Ccr2 的缺失减轻了类固醇激素失衡引起的尿功能障碍和前列腺巨噬细胞水平和胶原积累的改变。这些发现表明单核细胞浸润，导致巨噬细胞或其他细胞衍生物，在纤维化中起关键作用。
